Search Results (449)

Low back pain is closely associated with intervertebral disc (IVD) degeneration, in which inflammation and neovascularization within the annulus fibrosus (AF) contribute to pain generation. Platelet-derived growth factor (PDGF)-BB plays a crucial role in tissue repair and cellular homeostasis, but its role in AF cell biology remains poorly understood. To investigate the effects of PDGF-BB on human AF cells, healthy and degenerated AF cells were treated with PDGF-BB for 3 or 5 days, followed by bulk RNA sequencing. Functional enrichment of differentially expressed genes, transcription factor activity analysis, and protein–protein interaction network analysis was performed. Publicly available single-cell RNA-seq data were used to compare the transcriptomic profiles of native healthy and degenerated AF samples. In addition, TNF-α stimulation was conducted to validate the anti-inflammatory effects of PDGF-BB. Our findings suggest that PDGF-BB induced both common and context-dependent transcriptional responses in healthy and degenerated AF cells. In healthy AF cells, PDGF-BB consistently upregulated genes associated with cell cycle and developmental growth. In degenerated AF cells, PDGF-BB also induced these responses, while additionally it downregulated the genes related to extracellular matrix remodeling and collagen degradation. Meanwhile, PDGF-BB showed common effects in both healthy and degenerated cells by modulating the expression of genes within G protein-coupled receptor (GPCR) networks that are linked to complement, inflammation, and neurotransmitter signaling. In addition, PDGF-BB also suppressed the expression of genes involved in inflammatory-neurogenic signaling, including nerve growth factor (NGF), C-X-C motif chemokine ligand 12 (CXCL12), and apolipoprotein E (APOE). To relate these PDGF-BB induced responses to disc degeneration, we reanalyzed publicly available single-cell RNA-seq datasets from native human AF tissues and found that NGF-positive cells showed increased tumor necrosis factor (TNF)-α signaling activity. When AF cells were stimulated with TNF-α, PDGF-BB treatment significantly inhibited the expression of NGF, endothelin-1 (EDN1), and interleukin 6 (IL6) under both baseline and TNF-α-stimulated conditions. These results suggest that PDGF-BB modulates gene expression associated with inflammatory and neurogenic signaling as well as ECM remodeling in human AF cells, providing a transcriptomic insight into the PDGF-BB’s function in AF biology. Full article

Epidemiological and biological evidence indicate a close connection between Alzheimer’s disease (AD) and type-2 diabetes mellitus. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, has a major role in glucose metabolism, the dysregulation of which has been implicated in both diseases. We conducted a case-control association study in a sample of 439 non-diabetic patients with late-onset AD and 304 cognitively healthy, non-diabetic elderly controls to determine the potential risk for developing AD associated with SLC2A1 rs841847 polymorphism. The rs841847 C/C genotype occurrence was higher in the AD group (AD: 60.4%, controls: 50.7%), while the minor T allele-containing genotypes were more frequent among controls (AD: 39.6%, controls: 49.3%). A multivariate logistic regression model adjusted for age, sex, and apolipoprotein E (APOE) ε4 status (ε4 allele carriers versus non-carriers) demonstrated that carriers of the T allele had a significantly reduced risk for AD compared to C/C homozygotes (OR = 0.672; 95% CI: 0.493–0.916; p = 0.012). Although the rs841847 polymorphism has been linked to type-2 diabetes mellitus, the present study investigated this gene variant in AD for the first time. Our findings indicate a moderate protective effect for the rs841847 T allele on the susceptibility to AD. We demonstrated the rs841847 polymorphism as a candidate single nucleotide polymorphism for further examination as a predisposing genetic factor for AD. Full article

Food-induced anaphylaxis (FIA) is a life-threatening allergic reaction, while wheat-dependent exercise-induced anaphylaxis (WDEIA) is triggered by wheat ingestion plus cofactors. To elucidate their differences, we profiled serum extracellular vesicle (EV) proteomes from 240 participants, including WDEIA, FIA, oral allergy syndrome (OAS), and healthy controls. All blood samples were obtained at least one month after the most recent acute allergic reaction, using TMT-based LC-MS/MS with ELISA validation. A total of 583 EV proteins were confidently identified, revealing distinct immune features. Compared with controls, EV-derived C1-inhibitor (C1-INH) significantly decreased in both WDEIA and FIA, showing diagnostic potential for systemic anaphylaxis. Seventy-six proteins differed between WDEIA and FIA, with reduced apolipoprotein E (APOE) in FIA and elevated eosinophil cationic protein (ECP) in WDEIA, both exhibiting good discriminatory power. These findings indicate that serum EV proteomics can reveal unique immune signatures and identify C1-INH, APOE, and ECP as potential biomarkers distinguishing food-related anaphylaxis subtypes. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau^P301S transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner. Full article

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and prominent neuroimmune remodeling, but the contribution of macrophage and myeloid states across disease severity remains incompletely defined. We integrated bulk transcriptomic, single-cell RNA sequencing (RNA-seq), and spatial transcriptomic datasets to characterize AD-associated myeloid immune changes across Braak stage and disease status. Across datasets, M2-like macrophage and myeloid signatures showed progressive enrichment with increasing neuropathological severity and were accompanied by pathway changes related to macrophage proliferation, TGF-β signaling, and myeloid homeostasis. Immune-feature-based classifiers identified macrophage-related variables among the informative features distinguishing AD from controls. CellChat analyses further inferred that M2-like myeloid populations occupied communication-enriched positions in single-cell and spatial interaction networks, including apolipoprotein E (ApoE), CX3C chemokine signaling, and fibronectin 1 (FN1)-associated signaling contexts. Collectively, these findings indicate that M2-like myeloid programs are consistently associated with AD severity and neuroimmune network remodeling. Rather than establishing a causal disease driver, this study highlights M2-like myeloid signatures as candidate neuroimmune components that warrant experimental validation in human-relevant systems. Full article

Background: Targeting Apolipoprotein E4 (ApoE4) represents a frontier in Alzheimer’s disease therapeutics. This study investigates the therapeutic potential of a nutraceutical panel (Polydatin, trans-resveratrol, luteolin, and PEA) by exploring their interaction with the ApoE4 EZ-482 cavity. Methods: Using a dual-platform docking strategy (SwissDock and Schrödinger Maestro) across three structural constructs. Results and Discussion: We identified the full-length protein (1–299) as the optimal target, showing a robust correlation between normalized docking scores (Spearman ρ = 0.79). Crucially, biophysical analysis via dynamic light scattering (DLS) revealed that the ApoE4–oxLDL complex exhibits a ζ-potential of −10.97 mV, a state prone to pathological aggregation. Luteolin and PEA effectively altered this electrostatic environment, inducing significant positive shifts to +2.15 mV and +1.05 mV, respectively. The alignment between computational rankings and experimental ζ-potential perturbations supports the predictive reliability of our model. These findings suggest that nutraceuticals can modulate the ApoE4–oxLDL biophysical profile and highlight that a full structural context is mandatory for developing effective ApoE4-targeted interventions. Full article

Coronary microvascular dysfunction (CMD) has emerged as a crucial contributor to cardiovascular morbidity and mortality, particularly in patients with ischemia and non-obstructive coronary arteries (INOCA). The condition arises from a complex interplay of structural and functional abnormalities within the small coronary vessels, driven by underlying molecular mechanisms including endothelial nitric oxide synthase (eNOS) uncoupling, oxidative stress, and chronic inflammation. Lipid metabolism plays a central role in this pathology, especially in the setting of elevated low-density lipoprotein cholesterol (LDL-C). Furthermore, the protective capacity of high-density lipoprotein (HDL) is increasingly understood to depend on its functionality rather than absolute levels, as it can become dysfunctional and pro-inflammatory in pathological states. Emerging evidence has identified lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins as significant, independent contributors to microvascular injury. Comprehensive clinical assessment of microvascular dysfunction therefore requires integration of advanced lipid profiling, including apolipoprotein B (ApoB), [Lp(a)], and the triglyceride-glucose (TyG) index with invasive and non-invasive measures of coronary flow reserve to more precisely stratify risk. In this narrative review, we synthesize current observational, mechanistic, and early interventional data linking diverse lipid phenotypes to coronary microvascular dysfunction. We propose a concept of lipid-driven CMD endotypes, such as ApoB-/particle overload, dysfunctional HDL, Lp(a)-mediated risk, and metabolic/TyG-high states, and map these to a practical, mechanism-informed management framework. While intensive LDL-C lowering with high-intensity statins and combination therapy remains guideline-directed care for high-risk patients, evidence for dedicated microvascular benefit from newer lipid and cardiometabolic agents is still largely hypothesis-generating. A personalized approach that aligns lipid phenotyping, CMD endotyping, and existing guideline-based therapies may help refine risk assessment and inform future trials. Full article

Background: Vascular dysfunction and neurovascular inflammation are increasingly recognized as contributors to Alzheimer’s disease (AD) pathophysiology, particularly through interactions with tau-related neurodegeneration. Endothelial adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), play key roles in blood–brain barrier regulation and immune-vascular crosstalk, yet their relevance to long-term disease progression and established AD biomarkers remains incompletely understood. Methods: Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we examined associations between baseline cerebrospinal fluid (CSF) levels of VCAM-1 and ICAM-1 and clinical progression, CSF biomarkers, neuroimaging measures, and cognitive outcomes over up to 10 years of follow-up. This study included 294 participants (87 cognitively normal, 129 with mild cognitive impairment, and 78 with AD). Multivariable logistic regression was used to assess associations with diagnostic progression, and linear regression models examined relationships with baseline and longitudinal measures of tau, amyloid-β, hippocampal volume, Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) metabolism, and cognition. Models were adjusted for age, sex, apolipoprotein E epsilon 4 (APOE ε4) status, baseline diagnosis, and baseline CSF amyloid-β, with false discovery rate correction applied for multiple comparisons. Results: Baseline CSF VCAM-1 and ICAM-1 levels did not differ across diagnostic groups. However, higher baseline levels of both markers were nominally associated with increased odds of disease progression. Notably, ICAM-1 showed a strong and robust association with baseline CSF phosphorylated tau, which remained significant after multiple-comparison correction. VCAM-1 was also associated with tau pathology, though this did not survive correction. Neither marker was associated with baseline or longitudinal changes in hippocampal volume, FDG-PET metabolism, or cognitive performance. Conclusion: CSF VCAM-1 and ICAM-1 appear to reflect neurovascular inflammatory processes linked to tau pathology rather than markers of clinical stage or longitudinal neurodegeneration. These findings support a role for endothelial activation in AD pathophysiology and highlight vascular–immune mechanisms as potential contributors to tau-related disease vulnerability. Full article

Intracranial atherosclerosis (ICAS) is a distinct, inflammation-dominant vasculopathy and a leading cause of global stroke morbidity. Unlike extracranial atherosclerosis (ECAS), which often utilizes compensatory positive remodeling to maintain patency, ICAS is characterized by a unique architecture and a localized antioxidant gap that favor maladaptive negative remodeling. We critically analyze the molecular cascade initiated by the breakdown of the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) and the Krüppel-like factor 2/4 (KLF2/4) mechanotransduction axis, which triggers endothelial nitric oxide synthase (eNOS) uncoupling and establishes a state of chronic inflammation. This environment facilitates the subendothelial lipid retention of oxidized low-density lipoprotein (oxLDL), a process exacerbated by the intracranial deficiency of Apolipoprotein A-I (ApoA-I) and impaired glymphatic clearance. Crucially, we evaluate how these metabolic and mechanical insults drive vascular smooth muscle cell (VSMC) phenotypic switching; the transdifferentiation of contractile VSMCs into macrophage-like foam cells accounts for up to 60% of the plaque’s lipid-laden pool and destabilizes the fibrous cap. This vascular failure directly compromises the neurovascular unit (NVU), leading to pericyte dropout and blood–brain barrier breakdown. Beyond environmental stressors, we highlight the ring finger protein 213 (RNF213) variant as a critical genetic determinant of this susceptibility. Shifting the clinical paradigm from simple luminal narrowing toward the identification of the vulnerable plaque, we discuss how High-Resolution Vessel Wall Imaging (HR-VWI) and microRNA biomarkers can identify unstable lesions. By integrating these molecular and imaging signatures, we propose a precision medicine framework centered on the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NVU to effectively mitigate the high residual recurrence risk that persists under conventional therapy. Full article

Psoriasis patients face a significantly elevated risk of cardiovascular diseases (CVD), necessitating early and accurate risk prediction tools. This study developed and validated a machine learning model to predict CVD risk in psoriasis patients using clinical and biochemical data from 2685 individuals. After preprocessing and addressing class imbalance with SMOTE-NC, six machine learning models (Logistic Regression as baseline, XGBoost, LightGBM, CatBoost, GradientBoosting, AdaBoost) were evaluated using a completely leak-free nested cross-validation framework (outer k = 10, inner k = 3) with randomized hyperparameter search (n_iter = 50). Feature selection via the Boruta algorithm was performed separately within each training fold to prevent data leakage. The Boruta algorithm identified 21 key predictors, including age, systolic blood pressure (SBP), apolipoprotein B (apoB), fasting blood glucose (FBG), and complement C1q. CatBoost emerged as the top-performing model (OOF ROC-AUC = 0.908, 95% CI [0.892–0.924]; PR-AUC = 0.509, 95% CI [0.448–0.578]; F1 = 0.540; MCC = 0.498; Brier = 0.078), while the Logistic Regression baseline achieved ROC-AUC = 0.909 but was eliminated due to poor calibration (Brier = 0.114 > 0.10). All metrics were evaluated with 95% bootstrap confidence intervals (n = 1000 iterations). Explainable AI techniques (SHAP, LIME, Anchors) revealed that older age, elevated SBP, and metabolic dysregulation (e.g., high apoB, FBG) were the strongest CVD predictors. Local explanations were provided for five representative patients (high-risk, low-risk, and randomly selected), rather than a single instance, to better characterize model stability. Limitations include the single-center, retrospective design and lack of external validation. Future work should incorporate multi-ethnic cohorts and advanced biomarkers (e.g., genetic, imaging data) to enhance generalizability. This study demonstrates the potential of explainable AI to improve CVD risk stratification in psoriasis patients, offering a scalable tool for preventive cardiology. Full article

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting Aβ-responsive signatures in disease-associated microglia and reactive astrocytes while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell–cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the molecular complexity of RXR-mediated regulation, revealing the cellular origins of bexarotene’s known effects as well as novel, cell-type-specific responses. This study provides mechanistic insights into RXR-targeted interventions and supports APOE-associated pathways as promising therapeutic targets in AD. Full article

Apolipoprotein E4 (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Yet the molecular mechanisms underlying its contribution to AD remain to be fully elucidated. Here, we developed and characterized a set of apoE-specific single-domain antibodies (nanobodies) as a molecular toolbox to investigate intracellular apoE4. The nanobodies bind human apoE with nanomolar to sub-nanomolar affinity and recognize both apoE3 and apoE4. Domain-level epitope mapping revealed nanobodies that selectively bind either an N-terminal (residues 1–173) or C-terminal (residues 170–299) apoE4 fragment. Several nanobodies were validated as endoplasmic reticulum-targeted intrabodies that bind apoE4 intracellularly and promote its intracellular retention. These nanobodies constitute a versatile toolbox for probing and manipulating apoE4 in cellular models. As an exploratory application of this nanobody toolbox, we examined cytosolic apoE4, motivated by previous studies suggesting that cytosolic apoE4 fragments may influence AD-related cellular processes. Cytosolic expression of apoE4 resulted in perinuclear protein assemblies and the appearance of a ~25 kDa apoE4 fragment. Using a nanobody-based nuclear relocalization assay, we showed that cytosolic apoE4 remains accessible for nanobody binding but was not relocated to the nucleus by a nuclear localization signal-equipped nanobody. Altogether, this study introduces a nanobody-based toolbox to investigate apoE4 in distinct intracellular contexts, which can be relevant to AD. Full article

Pesticides are essential for modern agriculture but raise concerns about potential neurodevelopmental consequences, leading to bans in some countries. This study aimed to investigate the long-term effects of prenatal exposure to chlorpyrifos (CPF) on behavior and DNA methylation, considering genetic susceptibility via the apolipoprotein E (APOE) genotype. Pregnant mice—C57BL/6J and those carrying human APOE ε3 or ε4 alleles—were orally exposed to 0 or 1 mg/kg/day of CPF from gestational day 12 to 18. Adult offspring underwent light and dark and Morris water maze tests to assess anxiety-like behavior and spatial learning and memory. Then, hippocampal samples were collected to assess DNA methylation. Results indicated that body weight was lower in females and CPF-treated mice. C57BL/6J males spent less time in the light compartment, worsened by CPF. In contrast, within APOE genotype ε4 carriers spent more time in the light compartment, with CPF increasing male activity. Moreover, long-term retention was impaired in both male and female apoE4 mice prenatally exposed to CPF. DNA methylation analysis revealed sex-dependent differences, with hypomethylation in the CPF-treated male hippocampus. These findings highlight how pesticides and genetic factors interact, affecting neurobehavioral development, and explore the potential impact of CPF on DNA methylation. Full article

Traumatic brain injury (TBI) is being increasingly recognized as a major risk factor for chronic neurodegenerative disease, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD). Biomechanical forces during head trauma, particularly rotational acceleration and angular deformation, produce diffuse axonal injury (DAI) and widespread white matter damage that trigger persistent neurobiological cascades. These include axonal transport failure, blood–brain barrier (BBB) disruption, neuroinflammation, neurovascular and mitochondrial dysfunction, and pathological protein aggregation, closely paralleling core AD features. Epidemiological data support a dose–response relationship between TBI severity or repetition and subsequent dementia risk, moderated by genetic factors such as apolipoprotein E4 (ApoE4). Converging experimental and early clinical studies have begun to target shared injury and neurodegenerative pathways through acute neuroprotection, stem cell-based strategies for BBB restoration and neural repair, transcriptional and hormonal modulation, mitochondrial stabilization, and immunomodulation of chronic inflammation. This review synthesizes evidence linking biomechanical injury to molecular and neurovascular pathways of neurodegeneration and summarizes emerging temporally targeted interventions. By integrating mechanistic and therapeutic perspectives, we aim to narrow the translational gap between TBI and AD, refine identification of at-risk populations, and inform priorities for prevention and development of disease-modifying therapies. Full article

Traffic-related air pollution (TRAP) is known to contribute to oxidative stress in the central nervous system (CNS) and has been linked to increased risk of Alzheimer’s disease (AD). Alterations in the renin–angiotensin system (RAS), specifically increased angiotensin II (Ang II) signaling via the angiotensin II type 1 (AT₁) receptor, are implicated in increased oxidative stress in the CNS via activation of NADPH oxidase (NOX). As exposure to TRAP may further elevate AD risk, we investigated whether exposure to inhaled mixed gasoline and diesel vehicle emissions (MVE) promotes RAS-dependent expression of factors that contribute to AD pathophysiology in an apolipoprotein E-deficient (ApoE^−/−) mouse model. Male ApoE^−/− mice (6–8 weeks old) on a high-fat diet were treated with either an ACE inhibitor (captopril, 4 mg/kg/day) or water and exposed to filtered air (FA) or MVE (200 µg PM/m³) for 30 days. MVE exposure elevated plasma Ang II, inflammation, and oxidative stress in the hippocampus, associated with increased levels of Aph-1 homolog B (APH1B), a gamma-secretase subunit, and beta-secretase 1 (BACE1), involved in Aβ production. Each of these endpoints was normalized with ACEi treatment. These findings indicate that TRAP exposure in ApoE^−/− mice drives a RAS- and NOX-dependent oxidative and inflammatory response and shifts Aβ processing towards an amyloidogenic profile before overt Aβ deposition, suggesting a potential therapeutic approach for air pollution-induced AD risk. Full article